The long range goal of our research program is the development of delivery systems that will be effective for a variety of cancers. The major focus of these studies is to examine the use of non-viral gene transfer approach that can be used for immunotherapy protocols and its potential as a treatment of solid tumors. In vivo electroporation has shown a great deal of promise as a means of enhancing the expression of plasmid DNA in a variety of tissues including muscle, tumor, skin and liver. Previously, in vivo electroporation has been shown to be an effective way to enhance the effectiveness of chemotherapeutic agents in both pre-clinical and clinical studies. More recently, several studies have shown that delivering a plasmid coding for a cytokine in combination with electroporation can elicit an anti-tumor response. The specific research proposed in this application is intended to determine if the using in vivo electroporation to deliver a plasmid DNA coding for the cytokine IL-15 can be effective in treating metastatic melanoma. The study will be designed to accomplish the following specific aims: i. to evaluate B16.F10 melanoma growth or regression in response to electrically mediated IL-15 plasmid delivery. ii. To determine tumor and serum immune responses elicited after electrically mediated IL-15 plasmid delivery. iii. To evaluate the effect of intratumoral and intramuscular electrically mediated IL-15 plasmid delivery on the growth of metastatic melanomas, including both subcutaneous and lung lesions. iv. To evaluate the potential toxicity of electrically mediated IL-15 plasmid delivery for the treatment of melanoma. Successful completion of this project will demonstrate the potential role of IL-15 gene therapy delivered as a plasmid by electroporation as a therapy for melanoma. Public Health Relevance: The stimulation of the immune system through the administration of immunomodulatory agents such as cytokines to fight melanoma has been the focus of a number of studies. Unfortunately, these treatments usually have toxic side effects because of the high doses required and in most cases have not been completely effective. A method to decrease the toxicity of this type of treatment is to replace the high dose recombinant protein injections with plasmids expressing genes for one or more of these molecules and injecting either directly into the tumor or to the skin around the tumor or into the muscle. This study will examine if this strategy will work by utilizing a plasmid coding for IL-15 delivered directly into tumor cells.